One-pot synthesis of pyrano[4,3-b]quinolinones from 2-alkynyl-3-formylquinolines via oxidative 6-endo-dig ring closure

A new regioselective one-pot procedure to synthesize pyranoquinolinones from readily available 2-alkynyl 3-formylquinolines under mild NaClO₂/H₂O₂ conditions in good yields has been explored. This reaction sequence, involving oxidation followed by regioselective electrophilic 6-endo-dig cyclization is more efficient over the traditional Pd(0)-mediated synthesis. When scavenger-free conditions were used, unusual chlorinated furoquinolinone derivatives were obtained.     

Regioselective radical cyclization initiated by the reaction of allylic hydroperoxides with iron(II) sulfate

Treatment of 1-methyl-2-methylene-1-cyclohexyl hydroperoxide with a mixture of FeSO₄/CuCl₂ yielded 1-(1-chlorocyclohexyl)ethanone as the major product consistent with 6-endo-trig cyclization of the intermediate 5-acetylhex-5-enyl radical. This strategy was extended to the ring enlargement of a series of 1-isopropenylcycloalkyl hydroperoxides. Regioselective 7- or 8-endo-trig cyclization reactions could be achieved by treatment of the corresponding cyclopentyl or cyclohexyl hydroperoxides with either a mixture of FeSO₄/CuCl₂ or with FeSO₄ only. The influence of substituents on the efficiency of the 8-endo-trig cyclization process was also explored.     

Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles,aldehydes and alkynecarboxylic acids

We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted pyrimido [1,2-a]benzimidazoles, 2,4,10-trisubstituted 2,10-dihydropyrimido [1,2-a]benzimidazoles and 2,3-disubstituted imidazo [2,1-b]benzothiazoles via multicomponent reactions (MCRs) of heterocyclic azoles, aldehydes with easily storable and handling alkynecarboxylic acids. In the presence of a catalytic amount of CuI and K₂CO₃, the pyrimido [1,2-a]benzimidazole or imidazo [2,1-b]benzothiazole scaffold could be rapidly constructed through a 6-endo-dig or 5-exo-dig cyclization, respectively. The preliminary mechanistic study suggested that the formation of 2,3- disubstituted pyrimido [1,2-a]benzimidazoles, which completes the assembly of the scaffold and its C-3 position functionalization in one pot, undergoes a novel cascade process involving a decarboxylation, A [3] coupling, 6-endo-dig cyclization, nucleophilic addition and dehydration.     

Synthesis of novel spiro[benzo[4,5]thiazolo[3,2-a]chromeno[2,3-d]pyrimidine-14,3′-indoline]-1,2′,13(2H)-triones via three component reaction

A new and efficient method for the synthesis of hitherto unreported spiro[benzo[4,5]thiazolo[3,2-a]chromeno[2,3-d]pyrimidine-14,3′-indoline]-1,2′,13(2H)-triones was developed via the Domino Knoevenagel condensation–Michael addition–intermolecular cyclization sequences of isatin derivatives, cyclohexane-1,3-diones, and 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones, employing 12-tungstophosphoric acid (H₃PW₁₂O₄₀) as an effective and inexpensive catalyst.     

An expedient synthesis of indolo[1,2-a]quinolines via Mn(OAc)3-mediated oxidative free radical cyclization and NaI/O2-assisted dealkoxycarbonylation/aerobic oxidation cascade

An expedient synthetic procedure of indolo[1,2-a]quinolines was developed using a sequential Cu-mediated N-arylation of indole, Mn(OAc)₃-mediated oxidative free radical cyclization, and NaI/O₂-assisted concomitant dealkoxycarbonylation/aerobic oxidation. The last step was replaced by a palladium-catalyzed decarboxylation/elimination protocol for the allyl ester derivatives.     

Palladium-catalyzed synthesis of indane and cyclobuta[a]indenes from homoallylic alcohols derived from Baylis-Hillman adducts: base-dependent stereoselectivity for the benzylidene group in cyclobuta[a]indene

Various indane and cyclobuta[a]indene derivatives were synthesized by palladium-catalyzed cyclization of homoallylic alcohol derivatives prepared from Baylis-Hillman adducts. Especially, cyclobuta[a]indene derivative was synthesized stereoselectively by palladium-catalyzed 5-exo-trig/4-exo-trig cascade cyclization, albeit in moderate yield. The Z isomer was formed exclusively in the presence of Et₃N by usual Heck-type carbopalladation process while E isomer with Cs₂CO₃ most likely by a concerted metalation/deprotonation (CMD) process.     

A novel approach to 3-acylated indolizine structures via iodine-mediated hydrative cyclization

We have discovered a new route to 3-acylated indolizine structures via iodine-mediated hydrative cyclization. Reaction mechanism is proposed for this novel transformation, which involves a 5-exo-dig iodocyclization, deprotonation, incorporation of another iodo group, deprotonation, and subsequent replacement of the diiodo group by H₂O. Various 3-acylated indolizine derivatives were obtained using this mild procedure in good yields.     

Functional sulfur-containing compounds

The Thorpe-Ziegler intramolecular cyclization of 2-RCH₂S-, 2-RCH₂S(O)-, and 2-RCH₂SO₂-substituted nicotinic acid esters and nitriles (R is alkyl, aryl, and 2-thienyl) upon the action of potassium tert-butoxide has been studied. The reaction results in the formation of the corresponding 2-R-substituted 3-aminothieno[2,3-b]pyridines, 3-aminothieno[2,3-b]pyridine 1-oxides, and 3-aminothieno[2,3-b]pyridine 1,1-dioxides with the reaction taking place only in the case if R is aryl or 2-thienyl. Methyl esters of 2-RCH₂S-, 2-RCH₂S(O)-, and 2-RCH₂SO₂-substituted nicotinic acids also undergo the intramolecular cyclization of the Dieckmann type to form the corresponding 2-R-substituted 3-hydroxythieno[2,3-b]pyridines, thieno[2,3-b]pyridin-3(2H)-one 1-oxides, and thieno[2,3-b]pyridin-3(2H)-one 1,1-dioxides. Such a reaction takes place for all the R groups except when R = AlkCH₂S and AlkCH₂S(O).     

Direct access to 2-aminopyrazolo[1,5-a]pyridines via N-amination/cyclization reactions of 2-pyridineacetonitriles

We describe the straightforward synthesis of 6-substituted-2-aminopyrazolo[1,5-a]pyridines from 2-pyridineacetonitriles by N-amination with O-(mesitylsulfonyl)hydroxylamine and subsequent base-promoted cyclization. This N-amination/intramolecular cyclization reaction allows access to a variety of 6-substituted-2-aminopyrazolo[1,5-a]pyridines in a one-pot procedure, in moderate to good yields.     

Synthesis of poly-substituted pyrazolo[1,5-a]quinolines through one-pot two component cascade reaction

A diversity-oriented method for the synthesis of novel poly-substituted pyrazolo[1,5-a]quinolines has been developed on the basis of an S_NAr/Knoevenagel cyclization cascade reaction or an S_NAr/Dieckmann–Thorpe cyclization cascade reaction. The methods provide a variety of poly-substituted pyrazolo[1,5-a]quinolines bearing an amino, alkyl or aryl substituent at the 5-position. In addition, a diversity-oriented method for the synthesis of 2-substituted pyrazolo[1,5-a]quinolines from a readily available 2-[[(trifluoromethyl)sulfonyl]oxy]pyrazolo[1,5-a]quinoline has also been disclosed.     

One-pot synthesis of quinazolin-4(3H)-ones and fused quinazolinones by a palladium-catalyzed domino process

An efficient one-pot synthesis of quinazolin-4(3H)-ones, benzoimidazo[2,1-b]quinazolin-12(6H)-ones and imidazo[2,1-b]quinazolin-5(1H)-ones via a palladium-catalyzed domino process has been developed. The Pd-catalyzed reactions of 2-azidobenzamides 1 with isocyanides 2 produced quinazolin-4(3H)-ones 4 at room temperature by a domino Pd-catalyzed cross-coupling/carbodiimide-mediated cyclization. However, as 2-azido-N-(2-bromophenyl)benzamides 1 were used under heating condition in the presence of Cs₂CO₃, the benzoimidazo[2,1-b]quinazolin-12(6H)-ones 5 were directly obtained by twice Pd-catalyzed domino cyclization. A domino reogioselective 5-exo-dig intramolecular cyclization reaction of alkynyl-containing azides 6 with isocyanides 2 generated imidazo[2,1-b]quinazolin-5(1H)-ones 9 in 74–93% yields in the presence of catalyst Pd(PPh₃)₄ and K₂CO₃.     

Ruthenium-catalyzed cyclization of 3-en-1-ynyl imines with nucleophiles via tandem 5-exo-dig cyclization and nucleophilic addition

Treatment of 3-en-1-ynyl imines with TpRuPPh₃(CH₃CN)₂PF₆ catalyst (1 mol %) in DCE (50 °C, 6 h) effected catalytic cyclization with suitable nucleophiles and gave functionalized pyrroles in good yields. The reaction mechanism is proposed to proceed via (2-pyrrolyl)carbenoid intermediates derived from 5-exo-dig cyclization. This catalytic reaction works well with various nucleophiles, including water, alcohols and anilines.     

Synthesis of alicyclic esters via an intramolecular conjugate addition reaction. New method for generating (Z)-vinylcopper species from 1,1-dibromoalkenes

A novel cyclization reaction of a 1,1-dibromoalkene derivative having an α,β-unsaturated ester moiety was developed. Under the influence of Me₂CuLi, the 1,1-dibromoalkene was converted into a (Z)-vinylcopper species which in turn underwent an intramolecular conjugate addition reaction with the α,β-unsaturated ester moiety. Five-, six-, and seven-membered carbocycles were constructed by the present method. The substrate having an epoxide moiety also afforded a five-membered product via a 5-exo type intramolecular cyclization reaction.     

Synthesis of benzothieno[2,3-b]thiophenes, [2,3-b:3′,2′-d]-dithienothiophenes and their selenium derivatives via electrophilic cyclization and McMurry cyclization

Benzothieno[2,3-b]thiophenes, [2,3-b:3′,2′-d]-dithienothiophenes, and their selenium derivatives were synthesized in good yields from readily available 3-ethynyllithio-benzo[b]thiophenyllithio compounds, sulfur or selenium, and 2 equiv of acid chlorides. Two heteroarene rings were constructed by a twofold cyclization via an acid chloride-induced electrophilic ring closing and the McMurry cyclization using Zn/TiCl₄ reagents.     

3-exo-tet Cyclization of 2,2-disubstituted 1,3-dihalopropanes with indium in aqueous and ionic liquid solvent system

The 3-exo-tet cyclization of 2,2-disubstituted 1,3-dihalopropanes with In powder in THF solution of 20% H₂O, dioxane solution of 20% H₂O, and ionic liquids, such as [bmim]Br, [bmim]Cl, and [bmin]BF₄, respectively, was efficiently carried out to form the corresponding 1,1-disubstituted cyclopropanes in good yields. The cyclopropanation of 2,2-disubstituted 1,3-dihalopropanes with In powder in ionic liquids, such as [bmim]Br, [bmim]Cl, and [bmin]BF₄, was markedly accelerated compared with that in a THF solution of 20% H₂O and a dioxane solution of 20% H₂O. The mechanism was proposed to involve the radical 3-exo-tet cyclization of the formed 3-halopropyl radical.     

A cyclative cleavage approach to solid-phase synthesis of annulated pyrimidinones using Baylis-Hillman derivatives

An efficient and robust solid-phase synthesis of 6-substituted-2,5,6,8-tetrahydro-3H-imidazo[1,2-a]pyrimidin-7-ones, 3-substituted-1,3,4,6,7,8-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones and 3-substituted-3,4,6,7,8,9-hexahydro-1H-pyrimido[1,2-a][1,3] diazepin-2-ones from the acetates of Baylis-Hillman adducts employing Michael addition of diamines followed by intramolecular cyclization with cyanogen bromide and, finally, base promoted cyclative cleavage has been developed. The procedure is validated through an automated parallel synthesis of a small library of fourteen compounds of the 3H-imidazo[1,2-a]pyrimidin-7-one series.     

Michael additions of dihydropyrimidines and 2-amino-1,3,4-thiadiazoles to α,β-ethylenic compounds: using polyethylene glycols as a green reaction media

Polyethylene glycol (PEG) was found to be an inexpensive, non-toxic, and effective medium for the Michael additions of 3,4-dihydropyrimidines to α,β-ethylenic compounds to provide N3-functionalized dihydropyrimidines in the presence of K₂CO₃ as the catalyst. Under similar reaction conditions, 2-amino-5-aryloxymethyl-1,3,4-thiadiazoles reacted with methyl acrylate to give unexpected products 5H,6H-[1,3,4]thiadiazolo[1,2-a]pyrimidine-7-ones through tandem Michael addition and intramolecular cyclization.     

Stereoselective 5-exo-trig radical cyclization in the enantioselective synthesis of Pregabalin

A practical stereoselective 5-exo-trig radical cyclization procedure was developed in order to prepare enantiomerically pure GABA derivative precursors (4-alkyl-pyrrolidin-2-ones). This procedure allows much more rapid access to optically pure GABA derivatives, such as the powerful antiepileptic agent (S)-(+)-3-aminomethyl-5-methylhexanoic acid (Pregabaline).     

Electrophilic cyclization of 3-alkynyl-4-chalcogen-2-H-chromenes: synthesis of 3-halo-chalcogenophene[3,2-c]chromene derivatives

An efficient synthesis of 3-halo-chalcogenophene[3,2-c]chromene has been accomplished via electrophilic cyclization reaction of 3-alkynyl-4-chalcogen-2H-chromene using I₂, PhSeBr, and BuTeBr₃ as electrophilic sources. The cyclization reaction proceeded cleanly under mild reaction conditions, and 3-halochalcogen-chromenes were formed in good yields. In addition, the obtained 3-iodo-chalcogenophene-chromenes were readily transformed to more complex products using a metal-halogen exchange reaction with n-BuLi and trapping the lithium-intermediate formed with aldehyde, furnishing the desired secondary alcohol in good yield. Conversely, using the palladium catalyzed cross-coupling reactions with terminal alkynes and boronic acid, we were able to obtain the Sonogashira and Suzuki type products in good yields.     

Versatile synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of 2-alkynylbenzyl alcohols

An easy synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of readily available 2-alkynylbenzyl alcohols under neutral conditions is reported. Reactions were carried out at 70-100°C in the presence of catalytic amounts (1-2%) of PdI₂ in conjunction with 2 equiv. of KI for 1.5-24 h. The preference towards the 5-exo-dig cyclization mode (leading to 1,3-dihydroisobenzofurans) or the 6-endo-dig cyclization mode (leading to isochromenes) turned out to be dependent on the substitution pattern of the substrate as well as reaction conditions. In several cases, by properly adjusting the reaction conditions, the same substrate could be selectively converted into either the dihydroisobenzofuran or the 1H-isochromene derivative.